Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use

L-Citrulline is a non-essential but still important amino acid that is released from enterocytes. Because plasma levels are reduced in case of impaired intestinal function, it has become a biomarker to monitor intestinal integrity. Moreover, oxidative stress induces protein citrullination, and antibodies against anti-citrullinated proteins are useful to monitor rheumatoid diseases. Citrullinated histones, however, may even predict a worse outcome in cancer patients. Supplementation of citrulline is better tolerated compared to arginine and might be useful to slightly improve muscle strength or protein balance. The following article shall provide an overview of L-citrulline properties and functions, as well as the current evidence for its use as a biomarker or as a therapeutic supplement

Mucosal Monosaccharide Transporter Expression in Newborns With Jejunoileal Atresia and Along the Adult Intestine

OBJECTIVES: In newborn rodents, intestinal maturation involves delayed fructose transporter GLUT5 expression until weaning. In jejunoileal atresia (JIA), distal intestinal segments lack exposure to amniotic fluid-containing carbohydrates. We assessed in human newborns, the impact of intestinal maturation and obstruction on mucosal monosaccharide transporter expression. METHODS: Samples were obtained from 10 newborns operated for small intestinal atresia and from 17 adults undergoing gastroduodenoscopy and/or ileocolonoscopy. mRNA expression of the transporters SGLT1, GLUT1, GLUT2, GLUT5, and GLUT7 was measured in neonate samples proximal and distal of the atresia as well as in adult duodenum, ileum, and colon. Protein expression and localization was assessed using immunofluorescence. RESULTS: Although mRNA expression of monosaccharide transporters did not significantly differ between newborn and adult samples, luminal fructose transporter GLUT5 protein was absent in 0- to 4-day-old neonates, but expressed in adults. The mRNA expression of the 5 tested monosaccharide transporters was unchanged distal from the JIA relative to proximal. Similarly, luminal sodium-dependent glucose transporter SGLT1 and basolateral GLUT2 were expressed proximal and distal to JIA as visualized by immunofluorescence staining. With the exception of glucose transporter GLUT1 that showed highest expression levels in colon, all investigated hexose transporters showed strongest expression in duodenum, lower levels in ileum and lowest in colon. CONCLUSIONS: Human newborns lack small intestinal fructose transporter GLUT5 protein expression and small intestinal atresia does not affect the expression of hexose transporters

Plasma citrulline correlates with basolateral amino acid transporter LAT4 expression in human small intestine

Background & aims Plasma citrulline, a non-protein amino acid, is a biochemical marker of small intestine enterocyte mass in humans. Indeed, citrulline is highly correlated with residual bowel length in patients with short bowel syndrome. It is known to be synthesised in epithelial cells of the small intestine from other amino acids (precursors). Citrulline is then released into systemic circulation and interconverted into arginine in kidneys. If plasma citrulline concentration depends on abundance of intestinal amino acid transporters is not known. The aim of the present study was to explore whether plasma citrulline concentration correlates with the expression of intestinal amino acid transporters. Furthermore, we assessed if arginine in urine correlates with plasma citrulline. Methods Duodenal samples, blood plasma and urine were collected from 43 subjects undergoing routine gastroduodenoscopy. mRNA expression of seven basolateral membrane amino acid transporters/transporter subunits were assessed by real-time PCR. Plasma and urine amino acid concentrations of citrulline, its precursors and other amino acids were analysed using High Performance Liquid Chromatography measurements. Amino acid transporter mRNA expression was correlated with blood plasma and urine levels of citrulline and its precursors using Spearman's rank correlation. Likewise, urine arginine was correlated with plasma citrulline. Results Plasma citrulline correlated with the mRNA expression of basolateral amino acid transporter LAT4 (Spearman's r = 0.467, p = 0.028) in small intestine. None of the other basolateral membrane transporters/transporter subunits assessed correlated with plasma citrulline. Plasma citrulline correlated with urinary arginine, (Spearman's r = 0.419, p = 0.017), but not with urinary citrulline or other proteinogenic amino acids in the urine. Conclusions In this study, we showed for the first time that small intestinal basolateral LAT4 expression correlates with plasma citrulline concentration. This finding indicates that LAT4 has an important function in mediating citrulline efflux from enterocytes. Furthermore, urine arginine correlated with plasma citrulline, indicating arginine in the urine as possible additional marker for small intestine enterocyte mass. Finally, basolateral LAT4 expression along the human small intestine was shown for the first time